The key general objective of this proposal is a better understanding of the pathogenesis of the fetal alcohol syndrome (FAS). We will examine three aspects of this problem. First, we will determine whether ethanol inhibits the transfer of 2 key nutrients-zinc and biotin-across the human placenta. Deficiency of each of these nutrients in experimental animals is known to produce growth impairment and fetal malformation, hence, deficiency of either could contribute to FAS. There are virtually no data on normal transport of these substances by the human placenta and none on the effect of alcohol on this. Initially, we will define the normal characteristics of placental transport of these 2 substances. This will be done using the single perfused human placental cotyledon, isolated apical and basal human placental membrane vesicles, and cultured human placental trophoblast. The latter system permits longer (5 days) study. Having described normal transport, we will assess the effects of alcohol on transport of zinc and biotin. Second, cocaine ingestion too often accompanies ethanol consumption by pregnant women, and cocaine may impair fetal growth and development. To assess the potential for interaction between alcohol and cocaine in FAS we will study 3 aspects of cocaine handling in pregnancy. 1) We will initially determine the mechanism(s) by which cocaine crosses the human placenta and examine whether the tissue metabolizes this drug. 2) In as much as cocaine can suppress fetal liver growth, we will examine a possible mechanism: focusing on binding and processing of epidermal growth factor, an obligatory factor in the replication of these cells. The processing (internalization) of this factor is known to be impaired by ethanol. Now we will examine the role of cocaine and norcocaine (a known toxic metabolite) alone, as well as with ethanol, on EGF processing. These studies will be carried out in cultured rat fetal hepatocytes. 3) Cocaine commonly impairs adult cardiac function, but little is known about its effects on fetal heart. In rat fetal/neonatal cardiac myocytes in tissue culture we will correlate the effects of cocaine/norcocaine alone and with ethanol on heart contractility and 2 key processes-Ca++ influx and Na++ pump turnover. Finally, in pregnant monkeys we will assess, with Doppler ultrasound, the possibility that account may cause FAS by decreasing uterine/placental/fetal blood flow with resulting fetal hypoxia. These 3 approaches should contribute to better understanding of pathogenesis of FAS and the impact on the fetus of concomitant cocaine intake. FAS is a complex process, hence, the need for a comprehensive, multifactorial approach to its study.